This report includes work arising from the following clinical protocols: NCT00030147, NCT00060736, NCT00001231, and NCT00001322. The menopause transition is accompanied by a decrease in quality of life (QOL) measures for some women, and several randomized controlled trials of menopausal hormone therapy (HT) have targeted QOL as a potential indication for HT. Several community-based studies observed a significant reduction in QOL measures in perimenopausal women compared with women who were in the premenopause. In these studies, perimenopausal women reported more role limitations due to physical or emotional health, poorer perceived health, and more somatic symptoms (including pain) than premenopausal women. However, the presence of negative affective symptoms accounted for a high proportion of the variance in QOL measurements in the perimenopausal women (including disability related to physical symptoms). Thus, in community-based studies the presence of depression (PMD) in some perimenopausal women could be an important source of variability in measures of QOL at this stage of a womans life. We have characterized the impact of PMD on QOL, disability, social adjustment and role functioning. Our findings show that PMD is accompanied by a decreased QOL, decreased social adjustment and impaired role functioning comparable to depression and anxiety disorders occurring at other stages of a womans life. Neither perimenopausal reproductive status alone nor the presence of hot-flushes had a significant negative impact on QOL measures. PMD may also contribute to decreased QOL in community or clinic-based samples of perimenopausal women and, therefore, could account for observed differences in the therapeutic benefits of HT. It remains unclear whether the clinical characteristics we identified reflect pre-existing risk factors for depression during the perimenopause or the effects of a current depression. Future clinical and treatment studies in perimenopausal women should distinguish depressed women when outcome measures include QOL. The latter question was recently clarified by the results of our longitudinal study of women as they transition through the perimenopause. Specifically, we examined whether the changes in negative life events and declines in QOL measures observed in cross-sectional studies were antecedents of PMD or reflect the effects of the presence of depression. Thus, we prospectively evaluated healthy women longitudinally across the menopause transition. Seventy asymptomatic, premenopausal women, ages 41-55 years, were monitored longitudinally (clinic visits q 6-8 monthly) for an average of 5.2 years until 6-12 months after their final menses (FMP). Outcome measures included daily mood ratings, menstrual diaries, and at each clinic visit the Structured Clinical Interview for DSM-IV (SCID), plasma FSH levels, as well as standardized measures of QOL, marital satisfaction, and life events. Twenty-eight episodes of major (n=8) and minor (n=20) depression occurred in twenty-two women, twenty-seven of these episodes occurred in the 2-years surrounding the FMP. PMD was first-onset in nineteen women. Thus confirming reports by our group and others of the clustering of depressions during the late menopause transition a time associated with declining levels of ovarian estradiol secretion. During the four years prior to the FMP, compared to women who remained asymptomatic, women with PMD reported significantly lower life satisfaction in PMD but did not report significant differences in overall QOL, marital satisfaction, experience of personal loss, or negative life events. Plasma FSH levels also did not differ between those women who did and did not develop PMD. Thus, these data suggest that negative life events and decreased QOL/marital dissatisfaction do not uniformly precede the onset of PMD. Further, the relative absence of antecedent social or environmental in PMD suggests a more specific role for hormonal events in the triggering of PMD. The nature of the relationship between the onset of PMD and hormonal events of the perimenopause remains to be more fully characterized. Observational studies report the emergence of depressive symptoms after the discontinuation of estradiol therapy (ET) in 5-10% of women. We determined if sudden, blinded withdrawal of ET would precipitate depressive symptoms and if it would do so differentially in those with a history of PMD. Our findings support both predictions. Estradiol withdrawal precipitated depression in women with a history of PMD, but depressive symptoms emerged in neither women with no past history of PMD after estradiol withdrawal, nor in those women with past PMD who were maintained on ET. Importantly, the recurrence of depressive symptoms in women with past PMD occurred in the absence of differences in several measures that could influence mood, including baseline clinical characteristics (other than PMD), the severity of hot-flushes, and plasma hormone levels after withdrawal. The lack of depressive symptoms in the control women despite identical hormone manipulation (and similar levels of hot-flushes and plasma estradiol levels) demonstrates that estradiol withdrawal differentially impacts CNS function in some women so as to render them susceptible to depression. These observations, in the context of similar plasma reproductive hormone levels, suggest that normal changes in ovarian estradiol secretion can trigger an abnormal behavioral state in susceptible women. There are several mechanisms by which changes in estradiol might mediate the observed effects on mood. Estradiol and its receptors modulate the activity of virtually every system implicated in the pathogenesis of depression, including regulation of neurotransmitter synthesis and metabolism, stress axis activation, neuroplasticity (including regulation of BDNF), epigenesis, and immune system activation. Indeed, estradiol signaling through estrogen receptor (ER) beta reverses depressive-like behavior in animal studies. We are pursuing these questions in three projects as follows: First, we will initiate a new study investigating the ability of an ER-beta agonist (that crosses into the CNS) to prevent the emergence of depression after estradiol withdrawal in women with past PMD. Second, recently initiated studies focused on whether women with PMD have intrinsic cellular differences that result in a differential processing of the steroid signal within the CNS (similar to the biological differences we recently identified in women with another form of reproductive-related mood disorder, premenstrual dysphoric disorder see ZIAMH002865) Thus we have begun experiments employing lymphoblastoid and human induced pluripotent cells/neuroprogenitor cells from women with past PMD and controls to examine the molecular basis of the differential sensitivity to estradiol withdrawal. Finally, we have completed our studies examining hypothalamic pituitary-adrenal (HPA) axis function in PMD. Dysfunction of the HPA axis is a frequent accompaniment of depression, and HPA axis function is modulated by both aging and ovarian steroid secretion. Moreover, recent publications in the literature have identified HPA axis function as a substrate of risk in PMD. In contrast to these suggestions, we now, for the first time, demonstrate that the HPA axis response to the combined dexamethasone-corticotropin releasing hormone test do not distinguish women with PMD from control women. These findings suggest that reproductive endocrine-related mood disorders are not uniformly associated with the HPA dysregulation and could reflect underlying pathophysiologic processes that are distinct from those reported in women with non-reproductive-related depressions.